The project is designed to investigate the action of sulfonylureas and biguanides on the metabolism of fat and liver cells. Particular attention is also given to comparing their mechanisms of action with that of insulin on these cells. The possibility that the observed effects of sulfonylureas on these cells are secondary to an uncoupling of oxidative phosphorylation and that biguanides acts as inhibitor of electron transport will be examined. The anti-lipolytic action of these drugs on fat cells is apparently not secondary to inhibition of the formation of cyclic AMP. Rather sulfonylureas and biguanides appear to act by mechanisms similar to those of uncouplers and inhibitors of oxidative phosphorylation. In liver cells from starved rats a net increase in gluconeogenesis in the presence of alanine is seen after the addition of glucagon. The effects of sulfonylureas and biguanides on gluconeogenesis will be examined in liver cells. The proposed studies should provide further information on the mechanisms by which these drugs affect metabolism at the cellular level. Emphasis is also placed on the mechanisms by which insulin regulates the metabolism of isolated fat and liver cells. The role of cyclic nucleotides is the special emphasis at the moment but studies to date do not indicate that the mechanisms by which insulin and oral anti-diabetic drugs affect the metabolism of fat and liver cells is through regulation of cyclic AMP or GMP accumulation.